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Summary Asthma manifests as TH2-dominant airway inflammation regulated by inducible T-cell kinase (ITK). To investigate associations between genetic variants of the ITK gene and asthma, 31 single-nucleotide polymorphisms (SNPs) were genotyped in 303 normal controls and 498 asthmatics and the two groups were compared using logistic regression models. The functional effects of the ITK promoter SNP were assessed using pGL3 luciferase reporter systems and gel-shift assays. The minor allele−196C>T in the promoter region of the ITK gene was significantly more frequent in asthmatics than in controls. The luciferase activity of the PGL3-ITK-196T allele construct was higher than that of the −196C allele. In the gel-shift assay, −196T double-stranded oligonucleotides bound more strongly to Jurkat cell nuclear protein compared to the −196C double-stranded oligonucleotides. People with the −rare allele 196C>T may be more susceptible to asthma via transcriptional regulation of the ITK gene.

Patterns of Early Migration In order to gain insight into various migrations that must have happened during movement of early humans into Asia and the subsequent populating of the largest continent on Earth, the HUGO Pan-Asian SNP Consortium (p. 1541 ) analyzed genetic variation in almost 2000 individuals representing 73 Asian and two non-Asian populations. The results suggest that there may have been a single major migration of people into Asia and a subsequent south-to-north migration across the continent. While most populations from the same linguistic group tend to cluster together in terms of relatedness, several do not, clustering instead with their geographic neighbors, suggesting either substantial recent mixing among the populations or language replacement. Furthermore, data from indigenous Taiwanese populations appear to be inconsistent with the idea of a Taiwan homeland for Austronesian populations.

Objective To investigate single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) gene that have significant associations with the pathogenesis of polycystic ovary syndrome (PCOS) in a Korean population. Design Case-control study. Setting University-based hospital. Patient(s) One hundred thirty-four patients with PCOS and 100 healthy women as controls. Intervention(s) None. Main Outcome Measure(s) Frequencies of genotypes for SNPs in VEGF gene, which were specifically expressed in a Korean population. Result(s) After genotypic analysis, we found that among 10 SNPs, one novel SNP at site +9812 and one known SNP at site +13553 have P values lower than .05 (+9812: odds ratio [95% confidence interval] 0.61 [0.39–0.95]; +13553: odds ratio [95% confidence interval] 0.59 [0.37–0.93]) and one haplotype (ht4) also has a P value in the significant range (odds ratio [95% confidence interval] 0.34 [0.16–0.74]). Conclusion(s) We concluded that one novel SNP at +9812 site, one known SNP at +13553 site, and one selected haplotype in the VEGF gene have a high possibility of significant associations with the pathogenesis of PCOS in a Korean population.

Single nucleotide polymorphisms (SNPs) are the most abundant forms of human genetic variations and resources for mapping complex genetic traits and disease association studies. We have constructed a linkage disequilibrium (LD) map of chromosome 22 in Korean samples and compared it with those of other populations, including Yorubans in Ibadan, Nigeria (YRI), Centre d'Etude du Polymorphisme Humain (CEPH) reference families (CEU), Japanese in Tokyo (JPT) and Han Chinese in Beijing (CHB) in the HapMap database. We genotyped 4681 of 111,448 publicly available SNPs in 90 unrelated Koreans. Among genotyped SNPs, 4167 were polymorphic. Three hundred and five LD blocks were constructed to make up 18.6% (6.4 of 34.5 Mb) of chromosome 22 with 757 tagSNPs and 815 haplotypes (frequency ≥ 5.0%). Of 3430 common SNPs genotyped in all five populations, 514 were monomorphic in Koreans. The CHB + JPT samples have more than a 72% overlap with the monomorphic SNPs in Koreans, while the CEU + YRI samples have less than a 38% overlap. The patterns of hot spots an d LD blocks were dispersed throughout chromosome 22, with some common blocks among populations, highly concordant between the three Asian samples. Analysis of the distribution of chimpanzee-derived allele frequency (DAF), a measure of genetic differentiation, Fst levels, and allele frequency difference (AFD) among Koreans and the HapMap samples showed a strong correlation between the Asians, while the CEU and YRI samples showed a very weak correlation with Korean samples. Relative distance as a quantitative measurement based upon DAF, Fst, and AFD indicated that all three Asian samples are very proximate, while CEU and YRI are significantly remote from the Asian samples. Comparative genome-wide LD studies provide useful information on the association studies of complex diseases.

Coronary artery disease (CAD) is one of the most common forms of heart disease. It has been demonstrated that chemokine-mediated inflammation is associated with the development of CAD. In this study, in order to determine the role of CCR2, a receptor for MCP-1, in the development of CAD, we initially sequenced and identified the genetic variants of CCR2 using 24 unrelated Korean individuals' DNA samples. A total of 13 genetic variants, including 1 deletion and 12 SNPs, were identified in the Korean population. Although we could not detect any association of CCR2 polymorphic markers with CAD, several SNP markers of CCR2 gene showed highly significant signals with the number of arteries with significant coronary artery stenosis in the CAD male patients. The most significant signal was detected at the SNP located at exon 2 (+780T>C, Asn260Asn) CI: 1.19-1.87, P=0.0005 (odds ratio: 1.49, 95% CI: 1.19-1.87, p=0.0005) (Table 3). This result indicates that CCR2 can play a role in the pathogenesis of CAD, especially to the number of vessels in CAD.

Hemoglobin A(1c) (HbA(1c)) is an indicator of long-term glycemic control. The purpose of this study was to determine whether habitual snoring is associated with increased HbA(1c) levels in non-obese and normoglycemic middle-aged men and women. A total of 6981 subjects (3362 men and 3619 women) aged 40-69 years from the Korean Health and Genome Study were examined for the study. Each participant received a comprehensive physical examination as well as a set of questions pertaining to demographic characteristics and snoring frequency. Habitual snoring was defined as a snoring frequency ofor = 4 days week(-1). After adjusting for age, abdominal obesity, and other confounding covariates, male habitual snorers showed a 1.69-fold excess [95% confidence interval (CI) 1.30-2.19] odds of having a high HbA(1c) level. Similarly, premenopausal women with habitual snoring had a 2.31 times (95% CI 1.22-4.39) significantly higher odds of having elevated HbA(1c)levels compared with non-snorers. This association was not found in postmenopausal women. Multivariate analysis revealed that male habitual snorers aged 40-50 had a 2.08-fold excess (95% CI 1.40-3.09) risk of having an elevated HbA(1c) level. In male habitual snores over 50, the strength of association was attenuated. Our findings based on cross-sectional data support a hypothesis that habitual snoring is associated with impaired glucose tolerance even in non-obese and normoglycemic men and premenopausal women. However, as waist circumference as an index of abdominal obesity (visceral adiposity) in the present study may only partially represent the effect of visceral fat, there may be a residual confounding from visceral obesity in our result. Longitudinal follow-up studies are necessary to confirm the association between sleep-disordered breathing and impaired glucose tolerance and to examine the causal relationship in a healthy population without obesity and diabetes.

Objectives Despite recent increasing trends in cardiovascular morbidities and mortality in Asia, studies on short-term changes in cardiovascular risks remain limited. This study estimated 2-year incidence rates of hypertension in middle-aged Korean adults aged 40-69 years, and investigated the impact of baseline levels of blood pressure, body mass index, and other conventional risk factors on the progression to hypertension. Methods Blood pressures of participants were evaluated twice with a 2-year interval, measured by mercury sphygmomanometer according to the standardized protocol. Hypertension was defined when either the systolic and diastolic blood pressures were greater than 140 and 90 mmHg, respectively, or when a participant was treated with antihypertensive medications. Results The crude 2-year incidence (calculated per 100) of hypertension was 12.2; 13.0 for men and 11.6 for women. For those who had higher blood pressure at baseline examination, incidence rates were two-fold or five-fold higher compared with those with optimal blood pressure. Older age and overweight were also major predictors for hypertension, even in Koreans with a low serum cholesterol level. Conclusion This is the first investigation of short-term incidence rates of hypertension in Asia. The results are consistent with the recently reported increasing trends in cardiovascular mortality and morbidity in Asia.

Both of prolonged QT interval and elevated C-reactive protein (CRP) levels are known to be risk factors of cardiovascular disease. To our knowledge, few studies have reported the direct relationship between CRP levels and the QT interval in middle-aged population. The objective of the present study was to examine the association of CRP level with QT interval.A total of 2471 men and 2287 women from the Korea n Health and Genome study underwent physical examination and completed a questionnaire. A 12-lead electrocardiogram (ECG) recording was obtained from each subject. Subjects who were taking statins, non-steroidal anti-inflammatory drugs (NSAID) and postmenopausal hormone replacement therapy, which are known to have an effect on CRP levels, were excluded. Geometric means of CRP levels were compared among three groups, which were classified by heart rate-corrected QT (QTc) interval: prolonged (or =440 msec in men andor =450 msec in women), borderline (420-439 msec in men and 430-449 msec in women) and normal (420 msec in men and430 msec in women) groups. The means of CRP level in women, though over normal range, increased significantly as QTc interval was longer, independent of confounding factors, while those of men were on the borderline of significance. However, compared to normal range of QTc interval, prolonged QTc interval was associated with elevated CRP level, defined as more than 95 percentile of CRP, in men and women, respectively.Prolonged QTc interval in middle-aged men and women is associated with the elevated CRP, independent of confounding factors.

Interleukin (IL)-13, which is essential for IgE synthesis, mediates its effects by binding with a receptor composed of IL-4Ralpha and IL-13Ralpha1. We investigated the effects of IL-13 and IL-13Ralpha1 polymorphisms in Korean children with asthma, and whether these have been associated with IgE production. We enrolled 358 atopic asthmatic, 111 non-atopic asthmatic, and 146 non-atopic healthy children. IL-13 and IL-13Ralpha1 genotypes were identified using the PCR-RFLP method. There was an association between the asthma susceptibility and homozygosity for risk allele of IL-13 G+2044A. In children with atopic asthma, risk alleles in IL-13 (A-1512C and C-1112T) and IL-13Ralpha1 (A+1398G) showed increased total IgE (P=0.012, 0.015 and 0.017, respectively). Three-loci haplotype analysis for IL-13 showed that the haplotype composed of -1512C, -1112T and +2044A was associated with higher total IgE than other tested haplotypes in children with atopic asthma (P=0.003). The gene-gene interaction between risk alleles of each IL-13 promoter polymorphism and IL-13Ralpha1 polymorphism was associated with higher total IgE in children with atopic asthma (P=0.002, 0.010). These findings indicate that the IL-13 G+2044A is associated with asthma development and the IL-13 and IL-13Ralpha1 polymorphisms may interact to enhance IgE production.

The rupture of an intracranial aneurysm (IA) results in subarachnoid hemorrhage, a catastrophic neurological condition with high morbidity and mortality. Following-up on our previous genome-wide linkage study in Japanese population, we extensively analyzed a 4.6 Mb linkage region around D7S2472 on 7q11 by genotyping 168 single nucleotide polymorphisms (SNPs). SNP association and window scan haplotype-based association studies revealed a susceptibility locus for IA on a single LD block covering the 3'-untranslated region (3'-UTR) of ELN and the entire region of LIMK1. An association study with 404 IA patients and 458 non-IA controls revealed that the ELN 3'-UTR G(+659)C SNP has the strongest association to IA (P=0.000002) and constitutes a tag-SNP for an at-risk haplotype, which contains two functional SNPs, the ELN 3'-UTR (+502) A insertion and the LIMK1 promoter C(-187)T SNP. These allelic and haplotype-based associations were confirmed in a Korean population. Ex vivo and in vitro analyses demonstrate that the functional impact of both SNPs is the decrease of transcript levels, either through accelerated ELN mRNA degradation or through decreased LIMK1 promoter activity. Elastin and LIMK1 protein are involved in the same actin depolymerization signaling pathway; therefore, these lines of evidence suggest a combined effect of the SNPs in the at-risk haplotype possibly by weakening the vascular wall and promoting the development of IA.

Background Phenylketonuria (PKU) is an inborn error of metabolism that results from a deficiency of phenylalanine hydroxylase (PAH). We demonstrated PAH mutational spectrum from patients with PKU, including 10 novel and 3 tetrahydrobiopterin (BH4)-responsive mutations. In this study, 11 PAH missense mutations, including 6 novel mutations (P69S, G103S, L293M, G332V, S391I, A447P) found in our previous study, 2 mutations common in east Asian patients with PKU (R243Q, R413P), and 3 tetrahydrobiopterin (BH4)-responsive mutations (R53H, R241C, R408Q) have been functionally and structurally analyzed. Methods A transient protein overexpression system and an in vitro BH4-responsiveness study were used. The effects of PAH missense mutations on the PAH protein structure were also analyzed. To determine the conservation of 12 mutated residues, PAH was aligned using BLAST against full genomic sequences of 221 different species. Model structures of PAH protein and the composite tetramer were constructed using the software program, SHEBA. Results No PAH activity was detected for some mutants. However, the residual activities associated with other mutants ranged over a wide spectrum. The missense mutations responsive to BH4 were not highly conserved throughout the 43 species in the multiple sequence alignment that encode PAH. The composite model structure of PAH revealed that dimer stability was reduced in the BH4-responsive mutants, whereas tetramer stability remained normal. Conclusion This expression study analyzed PAH mutations and model structures of mutant PAH proteins are proposed. Correlation between the proposed mutant PAH structures and functions are suggested.

To examine the association between habitual snoring and components of the metabolic syndrome in Korean adults. Whether these associations are independent of obesity was also explored.Four thousand five hundred and six men and 5041 women aged 40-69 years from the Korean Health and Genome Study were examined. Information of snoring frequency was obtained by a questionnaire and components of the metabolic syndrome were measured.There was a clear dose-response relationship between the increasing frequency of snoring and the higher prevalence of each component of the metabolic syndrome (P0.001). After adjustment for age, abdominal obesity, and the other metabolic components, hypertension was significantly associated with a 1.2-fold excess of habitual snoring in both men (P0.05) and women (P0.05). The association of habitual snoring with hypertension was unaltered by obesity. Regardless of the presence or absence of abdominal obesity, there was an increase in the prevalence of habitual snoring as the number of metabolic abnormalities increased.Habitual snoring is associated with hypertension independent of obesity. While the relationship between habitual snoring and obesity is well recognized, characterization of the role of the other components of the metabolic syndrome as a cause or result of habitual snoring warrants a further study.

Background and Methods: Numerous genetic studies have mapped asthma susceptibility genes to a region on chromosome 5q31–33 in several populations. This region contains a cluster of cytokines and other immune-related genes important in immune response. In the present study, to determine the genetic variations and patterns of linkage disequilibrium (LD), we resequenced all the exons and promoter regions of the 29 asthma candidate genes in the chromosome 5q31–33 region. Results: We identified a total of 314 genetic variants, including 289 single nucleotide polymorphisms (SNPs), 22 insertion/deletion polymorphisms and 3 microsatellites. Standardized variance data for allele frequency revealed substantial differences in SNP allele frequencies among different ethnic groups. Interestingly, significant ethnic differences were observed mainly in intron SNPs. LD block analysis using 174 common SNPs with a frequency of >10% disclosed strong LD within most candidate genes. No significant LD was observed across genes, except for one LD block (CD14-IK block). Gene-based haplotype analyses showed that 1–5 haplotype-tagging SNPs may be used to define the six or fewer common haplotypes with a frequency of >5%, regardless of the number of SNPs. Conclusion: Overall, our results provide useful information for the identification of immune-mediated disease genes in the chromosome 5q31–33 region, as well as valuable evidence for gene-based haplotype analysis in disease association studies.

Aims Growing evidence supports the hypothesis that chronic low-grade inflammation related to innate immunity may play an important role in the pathophysiology of Type 2 diabetes mellitus (T2DM). The monocyte differentiation antigen CD14 gene (CD14) acts as the receptor for lipopolysaccharide (LPS) and augments monocyte/macrophage inflammatory responses. Methods We have sequenced the gene, including all exons, exon/intron boundaries, and the −1.5 kb of the 5′ flanking region. Two common loci (minor allele frequency > 0.05) were genotyped in 775 T2DM patients and 316 control subjects recruited in the Korean T2DM Study. Results Eight polymorphisms, including four non-synonymous forms, were identified in CD14. No polymorphisms were found in association with T2DM. However, one common promoter SNP (−260T>C) was significantly associated with both the serum triglyceride level (TG) and body mass index (BMI) in non-diabetic control subjects. Individuals who carried the minor allele (C) had higher TG levels (1.65 ± 0.81 vs. 1.46 ± 0.80 mmol/l; P = 0.0007) and BMI (23.96 ± 3.00 vs. 23.28 ± 3.22 kg/m2; P = 0.04) as compared with subjects carrying T/T genotypes. Conclusion Our data suggest that lipid metabolism and obesity, important pathophysiological elements of T2DM and the metabolic syndrome, are regulated by complex mechanisms that include the CD14 gene polymorphism-mediated genetic propensity to non-specific inflammatory responses.

Interrelationship between C-reactive protein (CRP) and metabolic syndrome (MS) was evaluated in a community-based cohort of 9773 Koreans aged 40–69 years. Metabolic syndrome was defined by criteria of the National Cholesterol Education Program. CRP was measured by validated high-sensitivity assay. The median CRP level was 1.4mg/1, and significantly increased as the number of components of MS increased (P trend r =0.18), triglyceride ( r =0.14), blood pressure ( r =0.11), HDL-cholesterol (r =−0.10), and fasting glucose ( r =0.09) (all P values

In this study, we describe a novel approach to human cancer therapy that is based upon trans-splicing ribozyme-mediated replacement of cancer-specific RNAs with new transcripts that exert therapeutic activities. We have developed a specific ribozyme that can reprogram human telomerase reverse transcriptase (hTERT) RNA to induce transgene activity selectively in cancer cells that express the RNA. The ribozyme-mediated triggering of the transgene expression was accomplished via a high-fidelity trans-splicing reaction with the targeted residue in the hTERT-expressing cells. The ribozyme also induced cytotoxic activity in various hTERT-expressing cancer cells, hence selectively retarding the growth of those cells. Efficient and specific cell regression was also detected with ganciclovir (GCV) treatment only in hTERT-positive cancer cells, which were established to express stably the specific ribozyme that contains the herpes simplex virus thymidine kinase (HSV-tk) gene. Tissue-specific expression of the ribozyme could further augment the target specificity of the ribozyme. Importantly, we observed efficient regression of tumors with GCV treatment in mice that had been inoculated subcutaneously with hTERT-positive cancer cells that stably expressed the specific ribozyme that contains HSV-tk. These results suggest that the hTERT RNA-targeting trans-splicing ribozyme could be a powerful agent for tumor-targeted specific gene therapy.

The chemokine (C-X-C motif) receptor 3 (CXCR3) gene, on chromosome Xq13, is known to have critical roles in inflammatory and immune responses. In an effort to discover polymorphisms have been implicated in asthma, we investigated the genetic polymorphisms in CXCR3 to evaluate it as a potential candidate gene for a host genetic study of asthma. Statistical analysis revealed that one SNP in intron 1, c.12+234G>A, showed significant association with the risk of asthma development (P = 0.007, OR = 0.81). By subgroup analyses stratified by gender and atopic status, the genetic effect of c.12+234G>A on asthma was more apparent among male atopic subjects (P = 0.0009, OR = 0.61). Our findings suggest that polymorphisms in CXCR3 might be one of the genetic factors for the risk of asthma development, especially in male atopic subjects. CXCR3 variation/haplotype information identified in this study will provide valuable information and insight into strategies for the control of asthma and its subgroup, atopy.

Here we report a large, extensively characterized set of single-nucleotide polymorphisms (SNPs) covering the human genome. We determined the allele frequencies of 55,018 SNPs in African Americans, Asians (Japanese-Chinese), and European Americans as part of The SNP Consortium's Allele Frequency Project. A subset of 8333 SNPs was also characterized in Koreans. Because these SNPs were ascertained in the same way, the data set is particularly useful for modeling. Our results document that much genetic variation is shared among populations. For autosomes, some 44% of these SNPs have a minor allele frequencyor =10% in each population, and the average allele frequency differences between populations with different continental origins are less than 19%. However, the several percentage point allele frequency differences among the closely related Korean, Japanese, and Chinese populations suggest caution in using mixtures of well-established populations for case-control genetic studies of complex traits. We estimate that approximately 7% of these SNPs are private SNPs with minor allele frequencies1%. A useful set of characterized SNPs with large allele frequency differences between populations (60%) can be used for admixture studies. High-density maps of high-quality, characterized SNPs produced by this project are freely available.

To compare geographical difference in the prevalence of isolated systolic hypertension (ISH) in between urban (Ansan) and rural (Ansung) Korean adults aged 40-69 years, 4351 men and 4604 women enrolled in the Korean Health and Genome Study were analysed. Information was collected regarding gender, alcohol intake, smoking status, household income, occupation, and years of education by trained interviewers. Eligible subjects included untreated hypertensive and normotensive subjects. ISH was defined as a systolic blood pressure (SBP)or = 140 mmHg and diastolic BP90 mmHg. The overall age-adjusted prevalence of ISH was 4.1%. The prevalence of ISH in Ansung (5.7%) was higher than in Ansan (2.5%, P0.05). Also it increased with increments of age, from 1.0 to 12.8% in Ansung (P0.05) and from 0.3 to 13.0% in Ansan (P0.05). In those with body mass index (BMI)or = 30.0 kg/m2 in Ansung, the prevalence of ISH in women was twice as much as in men. The prevalence of ISH in obese men and women with a waist-hip ratioor =1.0 andor = 0.85, respectively, was more than that of nonobese men and women in both areas. In Korea, because of industrialization, the age distribution was skewed and the Korean population in rural areas is more aged. ISH will become a truly major health problem in rural area, because ISH is related to age, BMI and waist-hip ratio. Therefore, the Korean government will be required to institute different policies in the hypertension management to target populations in rural and urban areas.

The tumor necrosis factor and TNF receptor (TNF-TNFR) superfamily plays very important roles in the pathogenesis of many immune-mediated diseases. Regulation of TNF-TNFR superfamily gene expression influences many aspects of the pathology associated with these diseases. In order to investigate genetic variations in the regulatory regions of the TNF-TNFR superfamily genes, promoter regions were screened by sequencing DNA samples from 24 unrelated Korean individuals. We identified a total of 68 single-nucleotide polymorphisms (SNPs) in the regulatory regions of the known TNF-TNFR superfamily genes, including 50 SNPs in the promoter regions, 16 SNPs in the 5'-UTR regions, and two SNPs in the coding regions of these genes. Among the 68 SNPs identified in this study, 25 SNPs were novel SNPs. Interestingly, the sequence alteration created by 11 SNPs completely abolished putative transcription factor binding sites in these alleles. These results suggest that these SNP sites can regulate gene expression by controlling the binding of transcription factors. The identification of function-altering SNPs in the promoter regions of the TNF-TNFR superfamily will facilitate efforts to understand the association of TNF-TNFR superfamily genes with several immune-mediated human diseases.

Objective: We investigated sequence variations of the 29-kb insulin-like growth factor 2 (IGF2) region in human chromosome region 11p15.5 in the Korean population. This region consists of IGF2, insulin-like growth factor 2 antisense (IGF2AS), and the insulin gene, all important candidate genes for various diseases, including cancer, obesity, diabetes, and coronary disease. While single nucleotide polymorphisms (SNPs) have been identified for this region and used in association studies, ethnic differences in genetic variation at this site have not been addressed. To date, SNPs for the entire 29-kb region in the Korean population have not been reported. Methods: We surveyed a population of 108 Koreans for SNPs in the 29-kb IGF2 region. Results: We identified 62 SNPs, consisting of 6 SNPs in the promoter region, 17 in the untranslated region, 19 in introns, and 20 in the intergenic region. We also analyzed linkage disequilibrium (LD) patterns and haplotypes using 36 high-frequency (> 5%)SNPs and found a well-defined LD block spanning about 13 kb that includes 8 kb of the IGF2AS gene, with two hot-spot regions flanking the LD block. Conclusion: These SNPs may be useful as genetic markers in disease association studies in the Korean population.

Background: The prevalence of undiagnosed airflow obstruction is difficult to measure since it requires screening in population-based samples to identify individuals free of clinical symptoms. The purpose of this report is to examine the prevalence of undiagnosed airflow obstruction and its relation with respiratory symptoms in middle-age adults in the Korean Health and Genome (KHG) Study. Methods: The KHG study is an ongoing population-based study of Korean adults aged 40 to 69 years. The current report includes 8,140 men and women without a pulmonary disorder or obstructive lung disease. In this sample, undiagnosed airflow obstruction was defined on the basis of spirometric testing and in the absence of a medical history or a recognized pulmonary disorder. Respiratory symptoms included chronic cough, chronic phlegm, wheezing, and shortness of breath. Results: Undiagnosed airflow obstruction was observed in 12.4% of the men (470 of 3,806 subjects) and in 3.5% of the women (152 of 4,334 subjects). In men, the age-adjusted prevalence of undiagnosed airflow obstruction increased consistently with increasing number of respiratory symptoms. In those who smoked, there was a 2.3-fold excess in its prevalence when three or more symptoms were present, as compared to when they were absent (27.4% vs 12.0%, p < 0.001). A 2.4-fold excess (20.6% vs 8.5%, p 0.004) was observed in nonsmoking men, in whom respiratory symptoms were consistently less common than in those who smoked. Respiratory symptoms were unrelated to undiagnosed airflow obstruction in women smokers, although only 3.9% smoked cigarettes. In women who were nonsmokers, the prevalence of undiagnosed airflow obstruction increased from 2.3% in those without a respiratory symptom to 6.0% when three or more symptoms were present (p 0.003). Conclusions: Findings suggest that undiagnosed airflow obstruction is common in Korea with several respiratory symptoms. Whether respiratory symptoms with associations with undiagnosed airflow obstruction can be used to design early intervention strategies that prevent or delay the onset of COPD and its disabling consequences warrants further study. (CHEST 2004; 126:1234–1240)

Single nucleotide polymorphisms (SNPs) are considered as very promising genetic markers for complex disease gene hunting. However, it has been demonstrated that there are significant ethnic differences in genetic variations. In order to investigate the genetic variations in the Korean population and their ethnic differences, a large number of SNPs of 161 disease candidate genes were collected from a publicly available SNP database and then tested for the distribution of allele frequency in the Korean population. Of all 458 SNPs tested, approximately 43.9% were polymorphic in the Korean population, whereas 44.5% were monomorphic. The remaining 11.6% were failed in the test. Significant differences have been observed when SNP allele frequency pattern of Koreans was compared with those of Caucasians and Africans, whereas this pattern was highly similar between Korean and Japanese populations. Our data indicate that although many of the SNPs available in publicly available database, especially coding-region SNPs (cSNPs), can be used as informative genetic markers for disease association studies, an extensive verification of public SNPs in a particular population studied should be undertaken prior to their association studies.

Endothelial progenitor cells (EPCs) were recently demonstrated to exist in human cord blood. Phytohaemagglutinin (PHA), a potent mitogen for mononuclear cells was used to induce EPCs from unsorted cord blood mononuclear cells (CBMCs). Adherent cells in clusters appeared approximately 24 h after CBMCs were cultured in plain Roswell Park Memorial Institute media containing 10% fetal bovine serum (culture media) and PHA. Adherent cells were further propagated for 1 week in plain culture media. Flow cytometry and Di-I staining analyses showed that CD45-, CD34+, Flk-1+, CD31+ or VE-cadherin+ EPCs were induced and that they were mainly from the CD34+ cell compartment. When enriched CD34+ cells alone were stimulated with culture supernatant of the PHA-activated CBMCs, they neither proliferated readily nor induced EPCs. Because EPCs first appeared within the clustering cells that expressed high levels of fibronectin and vascular endothelial growth factor (VEGF), our data suggest that both cell-cell/cell-matrix interaction and the local VEGF action are important in the induction of EPCs. Thus, we demonstrate for the first time that EPCs are induced from human cord blood stem cell populations that interact with neighbouring PHA-activated CBMCs. This finding may have a significant implication in inflammatory cell-mediated vasculogenesis and angiogenesis in vivo.

The search for differentially expressed genes in gastric cancer may help define molecular alterations and molecular diagnosis of gastric cancer. Using the differential display PCR technique, we identified 18 genes that are differentially expressed between normal and tumor human gastric tissues. Their expressions were verified with reverse Northern blot analysis and Northern blot analysis. Oxidative phosphorylation-related genes, antizyme inhibitor of ornithine decarboxylase, protein phosphatase-1beta, 35-kDa peroxisomal membrane protein, and cystic fibrosis transmembrane conductance receptor were highly expressed in tumor tissue, whereas pepsinogen A, Na-K ATPase alpha subunit, nerve growth factor receptor, and alpha-tropomyosin were highly expressed in normal tissue. In addition, 3 unknown genes were found to be differentially expressed in paired gastric tissues. These differentially expressed genes may provide significant opportunities for further understanding of gastric carcinogenesis and the molecular diagnosis of gastric cancer.

Asthma manifests as TH2-dominant airway inflammation regulated by inducible T-cell kinase (ITK). To investigate associations between genetic variants of the ITK gene and asthma, 31 single-nucleotide polymorphisms (SNPs) were genotyped in 303 normal controls and 498 asthmatics and the two groups were compared using logistic regression models. The functional effects of the ITK promoter SNP were assessed using pGL3 luciferase reporter systems and gel-shift assays. The minor allele-196CT in the promoter region of the ITK gene was significantly more frequent in asthmatics than in controls. The luciferase activity of the PGL3-ITK-196T allele construct was higher than that of the -196C allele. In the gel-shift assay, -196T double-stranded oligonucleotides bound more strongly to Jurkat cell nuclear protein compared to the -196C double-stranded oligonucleotides. People with the -rare allele 196CT may be more susceptible to asthma via transcriptional regulation of the ITK gene.

To identify the genetic bases for nine metabolic traits, we conducted a meta-analysis combining Korean genome-wide association results from the KARE project (n = 8,842) and the HEXA shared control study (n = 3,703). We verified the associations of the loci selected from the discovery meta-analysis in the replication stage (30,395 individuals from the BioBank Japan genome-wide association study and individuals comprising the Health2 and Shanghai Jiao Tong University Diabetes cohorts). We identified ten genome-wide significant signals newly associated with traits from an overall meta-analysis. The most compelling associations involved 12q24.11 (near MYL2) and 12q24.13 (in C12orf51) for high-density lipoprotein cholesterol, 2p21 (near SIX2-SIX3) for fasting plasma glucose, 19q13.33 (in RPS11) and 6q22.33 (in RSPO3) for renal traits, and 12q24.11 (near MYL2), 12q24.13 (in C12orf51 and near OAS1), 4q31.22 (in ZNF827) and 7q11.23 (near TBL2-BCL7B) for hepatic traits. These findings highlight previously unknown biological pathways for metabolic traits investigated in this study.

Purpose To determine the spectrum and frequency of rhodopsin gene (RHO) mutations in Korean patients with retinitis pigmentosa (RP) and to characterize genotype–phenotype correlations in patients with mutations. Methods The RHO mutations were screened by direct sequencing, and mutation prevalence was measured in patients and controls. The impact of missense mutations to RP was predicted by segregation analysis, peptide sequence alignment, and in silico analysis. The severity of disease in patients with the missense mutations was compared by visual acuity, electroretinography, optical coherence tomography, and kinetic visual field testing. Results Five heterozygous mutations were identified in six of 302 probands with RP, including a novel mutation (c.893C>A, p.A298D) and four known mutations (c.50C>T, p.T17M; c.533A>G, p.Y178C; c.888G>T, p.K296N; and c.1040C>T, p.P347L). The allele frequency of missense mutations was measured in 114 ethnically matched controls. p.A298D, newly identified in a sporadic patient, had never been found in controls and was predicted to be pathogenic. Among the patients with the missense mutations, we observed the most severe phenotype in patients with p.P347L, less severe phenotypes in patients with p.Y178C or p.A298D, and a relatively moderate phenotype in a patient with p.T17M. Conclusions The results reveal the spectrum of RHO mutations in Korean RP patients and clinical features that vary according to mutations. Our findings will be useful for understanding these genetic spectra and the genotype–phenotype correlations and will therefore help with predicting disease prognosis and facilitating the development of gene therapy.

The natural course of hepatitis B virus (HBV) infection is likely related to host immune factors. Interleukin-18 (IL-18) plays a significant role in immune defense. This study was undertaken to determine the association between the presence of hepatocellular carcinoma (HCC) and single-nucleotide polymorphisms (SNPs) in the IL-18 gene in HBV-infected patients. Between March 2002 and December 2004, 730 Korean subjects were enrolled in two different groups: (1) chronic carrier without HCC (n = 637) and (2) HCC (n = 93). We analyzed SNPs at four polymorphic sites in the IL-18 gene at positions −667G>T, −148G>C, +8925C>G, and +13925A>C in the study subjects. To evaluate the functional significance of SNPs in the IL-18 gene promoter region, we performed a reporter gene assay in HepG2 and Hep3B cells transfected with different alleles. The IL-18 −148C allele, +8925G allele, +13925C allele, and haplotype 3 (TCGC) were associated with the presence of HCC in codominant and dominant models. Furthermore, functional analyses using the reporter gene assay revealed that the −148C allele conferred significantly lower promoter activity. This study indicates that the −148C, +8925G, and +13925C alleles of the IL-18 gene are associated with the presence of HCC and the 148G>C SNP is functionally important in determining disease outcome.

To examine copy number variations among the Korean population, we compared individual genomes with the Korean reference genome assembly using the publicly available Korean HapMap SNP 50 k chip data from 90 individuals. Korean individuals exhibited 123 copy number variation regions (CNVRs) covering 27.2 mb, equivalent to 1.0% of the genome in the copy number variation (CNV) analysis using the combined criteria of P value (P < 0.01) and standard deviation of copy numbers (SD ≥ 0.25) among study subjects. In contrast, when compared to the Affymetrix reference genome assembly from multiple ethnic groups, considerably more CNVRs (n = 643) were detected in larger proportions (5.0%) of the genome covering 135.1 mb even by more stringent criteria (P < 0.001 and SD ≥ 0.25), reflecting ethnic diversity of structural variations between Korean and other populations. Some CNVRs were validated by the quantitative multiplex PCR of short fluorescent fragment (QMPSF) method, and then copy number invariant regions were detected among the study subjects. These copy number invariant regions would be used as good internal controls for further CNV studies. Lastly, we demonstrated that the CNV information could stratify even a single ethnic population with a proper reference genome assembly from multiple heterogeneous populations.

The outcome of hepatitis B virus (HBV) infection can be affected by host immune factors. Interleukin-18 (IL-18) was originally discovered as an interferon-γ-inducing factor and plays a critical role in immune response. We assessed the association between the clearance of HBV infection and single-nucleotide polymorphisms (SNPs) in the IL-18 gene. Between March 2002 and December 2004, a total of 1,050 Korean subjects were enrolled in the study and divided into two groups: (1) the HBV spontaneous recovery group (n = 320) and (2) the chronic HBV carrier group (n = 730). We analyzed SNPs at four polymorphic sites in the IL-18 gene at positions −667G>T, −148G>C, +8925C>G, and +13925A>C. We observed that the subjects bearing the IL-18 −148C allele [odds ratio (OR), 0.25; confidence interval (CI), 0.09–0.68; P = 0.01], the +8925G allele (OR, 0.36; CI, 0.15–0.88; P = 0.02), and the +13925C allele (OR, 0.25; CI, 0.13–0.82; P = 0.01) were significantly associated with HBV clearance in a recessive model. This study indicates that the −148C, +8925G, and +13925C alleles of the IL-18 gene are likely associated with HBV clearance in a Korean population.

The etiology and pathogenesis of type 2 diabetes mellitus (T2DM) are not completely understood although it is often associated with other conditions such as obesity, hypertension, and dyslipidemia. Lipoprotein lipase (LPL) is a key enzyme in human lipid metabolism that facilitates the removal of triglyceride-rich lipoproteins from the bloodstream. LPL hydrolyzes the core of triglyceride-rich lipoproteins (chylomicrons and very low density lipoprotein) into free fatty acids and monoacylglycerol. To gain insight into the possible role of LPL in T2DM, nine single nucleotide polymorphisms (SNPs) of LPL were analyzed for the association with T2DM using 944 unrelated Koreans, including 474 T2DM subjects and 470 normal healthy controls. Of the nine LPL SNPs we analyzed, a significant association with multiple tests by the false discovery rate (FDR) was observed between T2DM and SNP rs343 (+13836C>A in intron 3). SNP rs343 was also marginally associated with some of T2DM-related phenotypes including total cholesterol, high density lipoprotein cholesterol (HDLc), and log transformed glycosylated hemoglobin in 470 normal controls, although no significant association was detected by multiple tests. In total, our results suggest that the control of lipid level by LPL in the bloodstream might be an important factor in T2DM pathogenesis in the Korean population.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by insulin resistance and hyperglycemia. Leptin inhibits the glucose-stimulated insulin secretion, and leptin receptors are present on beta cells as well as on fat cells, thus enabling leptin to modulate both insulin secretion and action. Therefore, leptin (LEP) and leptin receptor (LEPR) genes could play a role in the regulation of glucose and insulin after an oral glucose load. For the association study of LEP and LEPR with T2DM and metabolic traits, 752 women from Seoul National University Hospital (SNUH data) and 532 women from the Korean Health and Genome Study (KHGS data) were selected. Using the SNUH data, we identified that LEP-632G>A and +4998A>C polymorphisms were marginally associated with T2DM, LEP+4950G>A was significantly associated with several metabolic traits, and LEPR+5193G>A, +7187A>C, +27265G>A, +35861T>C, and +52289A>G showed strongly significant association with body mass index (BMI). We observed reproducibility of these results using the KHGS data; LEP+4950G>A and +4998A>C were significantly associated with systolic blood pressure and low-density lipoprotein cholesterol level, respectively. In conclusion, we observed that several polymorphisms in LEPR that had previous reports of association with BMI were significantly replicated in our samples and newly found that some variations of LEP were associated with T2DM and metabolic traits.

Objective Coronary artery disease is caused by multiple genetic and environmental factors. The disease is also closely associated with cardiovascular conditions such as hypertension. In order to investigate any possible role of hypertension candidate genes in the disease development and progression, we examined the association of the polymorphisms of 31 hypertension candidate genes with coronary artery disease. Methods Genetic polymorphisms of 31 hypertension candidate genes were initially screened by resequencing DNA samples from 24 unrelated individuals in a Korean population. Association analysis was performed using 1284 unrelated Korean men, including 749 coronary artery disease subjects and 535 normal healthy controls. Results We identified a total of 409 single nucleotide polymorphisms including 40 nonsynonymous single nucleotide polymorphisms, 32 insertions/deletions and four microsatellites. Among 40 nonsynonymous single nucleotide polymorphisms, 29 were examined for an association with coronary artery disease. A significant association with coronary artery disease was observed in a polymorphism of the ADD1 gene (Gly460Trp; +29017G/T) (odds ratio 0.71-0.81; P = 0.01-0.04). The same polymorphism was also associated with the number of arteries with significant coronary artery stenosis in the coronary artery disease patients (P = 0.01) as well as the increase in systolic blood pressure (P = 0.02). Conclusions The ADD1 Gly460Trp polymorphism is significantly associated with an increased risk of coronary artery disease as well as blood pressure, indicating that ADD1 plays a role in the pathogenesis of coronary artery disease as well as hypertension.

The genetic effects of FLT3 polymorphisms on BMD and fracture risk in postmenopausal women were studied. We found that FLT3+13348C>T polymorphism and haplotype 2 were significantly associated with low BMD and high risk of fracture. Introduction: FMS-related tyrosine kinase 3 (FLT3) has been shown to play a critical role in the development of myelolymphoid progenitors and in the development of osteoclasts, but any possible genetic effect of FLT3 on bone metabolism has not been studied. Materials and Methods: To study a possible genetic effect of FLT3, we directly sequenced the FLT3 gene in 24 Korean individuals and identified 23 sequence variants. Seven polymorphisms were selected and genotyped in Korean postmenopausal women (n = 946). Results: We found that FLT3+13348C>T was associated with low BMD at the lumbar spine (p = 0.04) and femoral neck (p = 0.04). Haplotype analysis revealed that FLT3-ht2 (TTCTT) containing the rare allele in the +13348 position also showed significant association with low BMD in the lumbar spine (p = 0.04) and femoral neck (p = 0.05). Consistent with these results, the FLT3+13348C>T polymorphism and FLT3-ht2 were also significantly associated with high risk of fracture in the vertebrae (OR = 1.44–1.58; p = 0.03–0.04 and OR = 1.45–1.59; p = 0.02–0.03, respectively) and in any sites (OR = 1.34–1.81; p = 0.02–0.03 and OR = 1.34–1.81; p = 0.02–0.03, respectively). Conclusions: These results suggest that FLT3 polymorphisms play a role in determination of BMD and subsequent fractures in postmenopausal women.

Introduction: The Epstein–Barr virus transforms resting B cells into proliferating lymphoblastoid cells, the origin of cell lines. Method and results: Our cDNA microarray analyses led to the identification of 232 up‐regulated and 112 down‐regulated genes with more than a 3‐fold difference in lymphoblastoid cell lines compared to resting B cells. The functional classification of these genes exhibited the distinct expression signature for cell proliferation, cell cycle and an immune response. Among them, we verified the differential expression of several oncogenes such as stathmin 1 (STMN1), RAB27A, RAB9A, BACH1 and BACH2 using quantitative real‐time reverse transcriptase‐polymerase chain reactions or Western blot analysis. Expression of STMN1 (which is involved in regulation of the microtubule filament system, cell growth and S‐phase of cell cycle) was increased in lymphoblastoid cell line as well as in 7‐day post‐Epstein–Barr virus infection B cells, compared to resting B cells. Conclusion: Thus, this study suggests that Epstein–Barr virus infection induces STMN1 expression, which play a role in cell cycle progression and proliferation in the human B lymphocyte.

Dendritic cells (DCs), the most abundant antigen-presenting cells in the lung, have been drawing attention for their roles in specific allergic responses to aeroallergens with support of Th lymphocytes, and in persistent inflammatory changes in allergic asthma. To identify genetic factors that may be involved in the asthma susceptibility and development of the disease phenotypes, we examined association of DC-specific DCNP1 polymorphisms with the disease risk. The case-control study revealed association of the nucleotide variants with serum immunoglobulin E (IgE) levels specific for Dermatophagoides farinae (Der f 1) and Dermatophagoides pteronyssinus (Der p 1), major aeroallergens of dust mites, among subjects with asthma. In particular, the T-allele-carrying genotype frequencies for one of the variants (c.-1289C>T) located in the promoter region were found increased in the asthmatic group with low levels of the mite-specific IgE (odds ratio (OR)=0.63 (0.48-0.83) for Der p 1). Results from functional analyses indicated that the promoter variant would affect the gene expression by modulating DNA-protein interaction. We propose that the genetic polymorphism of DCNP1 may influence production of specific IgE by altering DC functions in the mite allergen presenting and/or processing. The functional relevance of the genetic variation would provide an important insight into the genetic basis of allergic response to the mite antigens.

Introduction: ITGA1 is involved in the early remodeling of osteoarthritic cartilage and plays an essential role in the regulation of mesenchymal stem cell proliferation and cartilage production. We investigated the association between bone parameters and ITGA1 polymorphisms and their haplotype linkage disequilibrium (LD) blocks (BL_hts). Genetic susceptibility to osteoporosis was studied in 946 postmenopausal Korean women. Methods: We identified 67 genetic polymorphisms in ITGA1 region by direct sequencing (n=114). Eight SNPs were genotyped to further investigate their potential involvement in osteoporosis in postmenopausal women (n=946). Areal BMD of the lumbar spine and proximal femur was measured using dual-energy X-ray absorptiometry. Results: The SNPs, +73187CNT (exon 3) and +76969TNG (intron 5), and their BL_hts were associated with bone mineral density (BMD) at various femur sites (p=0.009–0.05). Moreover, +159174ANC (intron 28) and its haplotype BL3_ht1 showed a highly significant association with risk of non-vertebral fracture (p=0.002–0.005) and the minor allele of +159174ANC showed a protective effect. Conclusions: These results are suggestive of the association of ITGA1 with osteoporosis and related risk in postmenopausal women.

Oxidative stress has been recently suggested to play a part in the development of osteoporosis. Catalase is a major antioxidant enzyme that detoxifies hydrogen peroxide by converting it into water and oxygen, thereby preventing cellular injury by oxidative stress.To examine the associations between the catalase gene (CAT) polymorphisms and bone mineral density (BMD) and bone turnover markers in postmenopausal Korean women.All exons, their boundaries and the promoter region (approximately 1.5 kb) were directly sequenced in 24 individuals. Among 18 variants identified by a direct sequence method, four polymorphisms were selected and genotyped in all study participants (n = 560). BMD at the lumbar spine and proximal femur was measured using dual-energy x ray absorptiometry. Serum osteocalcin concentrations and bone-specific alkaline phosphatase activity were determined by an immunoradiometric assay and an immunoassay, respectively.The mean (standard deviation) age of the participants was 59.4 (7.2) years. Multivariate analysis showed an association of the +22348C--T polymorphism with BMD at the lumbar spine (p = 0.01 in the dominant model) and at femur neck (p = 0.05 in the dominant model), and with serum osteocalcin level (p = 0.008 in the dominant model). Haplotype analyses showed that HT4 (-20T, +144C, +22348T, +33078A) was significantly associated with higher BMD at various sites (p0.001-0.03) and with lower serum osteocalcin levels (p = 0.01 in the codominant model).These findings indicate that the +22348C--T polymorphism and HT4 of CAT may be useful genetic markers for bone metabolism.

Objective To investigate several single nucleotide polymorphisms (SNPs) in the insulin receptor ( INSR ) gene that have significant associations with pathogenesis of polycystic ovary syndrome (PCOS) in a Korean population. Design Case-control study. Setting University-based hospital. Patient(s) 134 patients with PCOS and 100 healthy women as controls. Intervention(s) All exons of INSR in DNA samples from 100 healthy women and 134 women with PCOS were sequenced and compared. Main Outcome Measure(s) Frequencies of genotypes for several SNPs in INSR gene that were found as specifically expressed SNPs in a Korean population. Result(s) Among nine SNPs analyzed in a large population, the genotypic frequencies of eight SNPs were similar, and they had no statistically significant association with PCOS. However, the frequency of a minor allele for one novel SNP, +176477 C>T, was higher in the control group than the patient group. Conclusion(s) Among the analyzed SNPs, +176477 C>T, a novel SNP in the INSR gene, was associated with the pathogenesis of PCOS in a Korean population.

Bone mineral density (BMD) is a major factor for determining bone strength and osteoporotic fracture risk, and is determined by environmental and multiple genetic factors. KIT, which encodes a transmembrane receptor with tyrosine kinase activity, plays an important role in the differentiation of osteoclasts. We examined the associations between KIT gene polymorphisms and BMD in postmenopausal Korean women. All exons, their boundaries, and the promoter region (approximately 1.5 kb) from 24 individuals were directly sequenced. Eighteen polymorphisms were identified, and three single-nucleotide polymorphisms (SNPs) were genotyped in all study participants (n = 946). BMD at the lumbar spine and femoral neck was measured using dual-energy X-ray absorptiometry. The mean age of the study subjects was 58.9 ± 7.5 years, and the mean number of years since menopause was 9.6 ± 7.9 years. None of the three SNPs (−1694G>T, +41894A>G, and +49512G>A) was significantly associated with BMD value. However, multivariate analysis showed that the ht3 (−1694T-+41894A-+49512G) was significantly associated with lower BMD at the femoral neck (P = 0.007 in the recessive model). These findings indicate that KIT-ht3 may be a useful genetic marker for osteoporosis and that KIT may have a role on bone metabolism in humans.

A human bacterial artificial chromosome (BAC) library was constructed with high molecular weight DNA extracted from the blood of a male Korean. This Korean BAC library contains 100,224 clones of insert size ranging from 70 to 150 kb, with an average size of 86 kb, corresponding to a 2.9-fold redundancy of the genome. The average insert size was determined from 288 randomly selected BAC clones that were well distributed among all the chromosomes. We developed a pooling system and three-step PCR screen for the Korean BAC library to isolate desired BAC clones, and we confirmed its utility using primer pairs designed for one of the clones. The Korean BAC library and screening pools will allow PCR-based screening of the Korean genome for any gene of interest. We also determined the allele types of HLA-DRA and HLA-DRB3 of clone KB55453, located in the HLA class II region on chromosome 6p21.3. The HLA-DRA and DRB3 genes in this clone were identified as the DRA*010202 and DRB3*01010201 types, respectively. The haplotype found in this library will provide useful information in future human disease studies.

The number of cases of the metabolic syndrome is increasing dramatically in Western countries. However, the evaluation of the metabolic syndrome is limited in Asian countries. Thus, our objectives were: 1) to investigate parameters of the metabolic syndrome defined by the National Cholesterol Education Program (NCEP)-Adult Treatment Panel III (ATPIII) in the subjects representing Korean general population and 2) the modification of which factor is most effective in reducing the metabolic syndrome. A total of 10,044 (5024 rural and 5020 urban) Korean men and women in the age range 40–69 yr voluntarily participated in this community-based cross-sectional study (a rural and an urban community was selected). Anthropometric parameters (weight, height, waist and hip circumference and blood pressure), social factors (smoking, alcohol, exercise and education status) as well as biochemical parameters (fasting glucose and insulin, lipids and body composition) were measured. Twenty-six point one per cent of the total subjects were classified as having the metabolic syndrome. Age- and sex-adjusted prevalences were 29.3 and 22.3% in the rural and urban community, respectively (p

The success of the Human Genome Project and recent technological progress have made the analysis of individual genetic variation much more feasible. However, genetic variations responsible for common complex human diseases and traits are largely unknown, with a few exceptions of specific subtype of common diseases (e.g. early onset type diabetes or Alzheimer disease). 1 Twin study has evolved from the classical twin study design, in which comparison of concordance in traits or diseases between monozygotic and dizygotic twins provided evidence about the genetic and environmental contributions to the phenotypes/diseases of interest. 2 Current twin studies in Europe, Australia, and other countries are already comprehensive genomic studies rather than a classical twin design, which maximize the presence of twins. Examples of innovation include: linkage study using dizygotic twin pairs; linkage and association study using the family of twins; epigenetic study using monozygotic twins; and tests for gene–environmental

Plexin A2 (PLXNA2) is a receptor that recognizes secreted or membrane-bound semaphorin 3A, which is implicated in neural regulation of bone metabolism. In the present study, we identified 48 genetic polymorphisms in PLXNA2 by resequencing, and 10 single nucleotide polymorphisms (SNPs) were selected for further investigation into their potential involvement in osteoporosis in a postmenopausal population (n=560). Two SNPs, +14G>A (Gln5Arg) and +183429C>T (Tyr1621Tyr), and Block1-ht2 were associated with risk of vertebral fracture (p=0.01–0.05), and three SNPs, +799G>A (Ala267Thr), +135391G>A, and +190531G>C, were associated with bone mineral density at various femur sites (p=0.003–0.03). Particularly, the minor allele of +14G>A was associated with a protective effect on vertebral fracture and higher lumbar bone mineral density, suggesting that +14G>A may be a useful marker for osteoporosis and its related fracture. These results provide, for the first time, evidence supporting the association of PLXNA2 with osteoporosis in postmenopausal women.

Although the prevalence of chronic obstructive pulmonary disease (COPD) and its relationship with respiratory symptoms are well documented, few studies have focused on individuals with normal lung function, particularly in developed regions of Asia. The purpose of this report is to examine the relationship between respiratory symptoms and FEV1 in a population-based sample of Korean men and women with normal lung function. Subjects comprised 7518 individuals aged 40–69 years without airflow obstruction based on spirometric testing and in the absence of a medical history of pulmonary disease. Respiratory symptoms included chronic cough, chronic phlegm, wheezing, and shortness of breath. In men, the age-adjusted mean FEV1 was lower by 165 ml in smokers and 133 ml in nonsmokers in the presence versus the absence of wheezing (p < 0.05). While walking at a usual pace, FEV1 in smoking men was 210 ml lower in the presence versus the absence of shortness of breath (p < 0.05). Among nonsmoking men, overall shortness of breath and shortness of breath while walking uphill were associated with a lower FEV1 by 56 and 80 ml, respectively) versus those who reported having no shortness of breath (p < 0.05). Respiratory symptoms were unrelated to FEV1 in women smokers, although only 3.5% smoked cigarettes. In nonsmoking women, FEV1 was lower by an average of 89 ml in the presence versus the absence of wheezing (p < 0.001). Nonsmoking women also had a lower FEV1 in the presence of shortness of breath (overall, while at rest, and while walking uphill or at a usual pace, p < 0.001). Our findings suggest that respiratory symptoms are associated with a lower FEV1 in men and nonsmoking women with normal lung function. Whether respiratory symptoms can be used to identify individuals at risk for developing COPD needs further study.

Bone mineral density (BMD), the major factor determining bone strength, is closely related to osteoporotic fracture risk and is determined largely by multiple genetic factors. Semaphorin 7a (SEMA7A), a recently described member of the semaphorin family, has been shown to play a critical role in the activation of monocyte/macrophages that share progenitors with bone-resorbing osteoclasts and thus might contribute to osteoclast development. In the present study, we directly sequenced the SEMA7A gene in 24 Korean individuals, and identified 15 sequence variants. Five polymorphisms (+15667GA, +15775CG, +16285CT, +19317CT, +22331AG) were selected and genotyped in postmenopausal Korean women (n = 560) together with measurement of the areal BMD (g/cm2) of the anterior-posterior lumbar spine and the non-dominant proximal femur using dual-energy X-ray absorptiometry. We found that polymorphisms of the SEMA7A gene were associated with the BMD of the lumbar spine and femoral neck. SEMA7A + 15775CG and SEMA7A+22331AG were associated with low BMD of the femoral neck (P = 0.02) and lumbar spine (P = 0.04) in a recessive model. SEMA7A-ht4 also showed an association with risk of vertebral fracture (OR = 1.87-1.93, P = 0.02-0.03). Our results suggest that variations in SEMA7A may play a role in decreased BMD and risk of vertebral fracture.